The present invention relates to a method to inhibit HIV infection by using an antibody to estrogen-stimulated leucine aminopeptidase (es-LAPase) or one or more inhibitors of es-LAPase activity, or a combination thereof. The invention further relates to a method to inhibit HIV infection by using an antibody to es-LAPase, one or more inhibitors of es-LAPase activity and an anti-estrogen compound. Novel compositions which inhibit HIV infection are also part of the present invention.
In spite of having achieved an in depth and comprehensive genetic structure of the human immunodeficiency virus (HIV) and of that of its several structural and geographical clusters, a very limited success in the prevention and treatment of AIDS has been attained. Although HIV and its variants are well characterized as the prime causative agents leading to the human acquired immunodeficiency syndrome (AIDS), a less comprehensive identification of key cellular factors involved in the early molecular mechanisms leading to viral entry have been accomplished.
CD4 T-cells are the principal target of HIV infection as shown from both in vitro and in vivo studies. The CD4 glycoprotein at the surface of T-cells exhibits a high affinity for HIV virions. Other molecules, particularly from the chemokine-receptor family, also participate to promote viral entry into target cells.
Therapeutics modalities to thwart the progress of the disease in HIV infected patients relies principally on two types of medications: Reverse transcriptase inhibitors and protease inhibitors. Although successful at slowing the replication of the virus, they are limited by the high rate of mutagenesis in the virus which results in modification of the drugs"" binding site and their concomitant lost of efficacy. One approach to resolve the problem has been to administer several drugs simultaneously to lower the probability of the development of resistant strains of the virus. However, these multidrug regimen create serious side effects. As a result compliance may be low.
Furthermore, current therapies for HIV infections are not specific for particular groups of individuals such as women. In a recent report it was found that the number of women infected with HIV during 1991 and 1995 increased by 63%, more than any other group of people that had contracted AIDS, regardless of race or mode of exposure to HIV virus [Centers for Disease Control and Prevention. (1996). HIV/AIDS Surveill. Rep. Centers for Disease Control and Prevention; 8. Atlanta, Ga.]. The increased incidence of AIDS epidemic on morbidity and mortality among women (ages of 25-44) has been recently confirmed by other groups [Wortley, P. M., and Flemming, P. L. (1997). AIDS in Women in the United States: Recent Trends. JAMA, 278: 911-916.]. The reasons for the increased incidence of AIDS in women are largely unknown. Not only women are more prone to infection than men (supra) but studies have shown that anti-HIV drugs work differently in women and men. For example, toxicities, side effects and blood levels have been shown to be gender specific. Hormonal differences between men and women are cited to explain the differences but no clear link has been established. In view of the above data, there is a need to tailor therapeutic modalities to exploit the differences in the infection process between men and women to improve the efficiency of treatments.
Independently of the role of CD4, the putative receptor for HIV and that of the xcex2-chemokine co-receptors (CKR-5, CCR5 and CXCR-4), we have described the important role of both membrane-bound and extracellular Leucine Aminopeptidase in HIV viral entry. (Pulido-Cejudo, G. et al. (1997) Antiviral Research 36, 167-177).
The present invention overcomes the limitation of the prior art by providing a link between LAPase activity and estrogen. This link has been exploited herein to discover new HIV viral inhibitors which can be used alone or in combination with improved efficacy.
The present invention relates to a method to inhibit HIV infection by using an antibody to es-LAPase or an inhibitor of es-LAPase activity, or a combination thereof. The invention further relates to a method to inhibit HIV infection by using an antibody to es-LAPase, an inhibitor of es-LAPase activity and an anti-estrogen compound. Novel compositions which inhibit HIV infection are also part of the present invention.
Thus according to the present invention there is provided a method for reducing HIV infectivity towards T lymphocytes comprising contacting said T lymphocytes with a sufficient amount of an inhibitor of LAPase.
In a further embodiment of the present invention there is provided a method for reducing HIV infectivity towards T lymphocytes comprising contacting said T lymphocytes with a sufficient amount of an antibody specific for LAPase, more specifically a monoclonal antibody specific for es-LAPase.
This invention also provides a method for reducing HIV infectivity towards T lymphocytes comprising contacting said T lymphocytes with a sufficient amount of an antibody specific for es-LAPase and an inhibitor of LAPase.
This invention also provides a method for reducing HIV infectivity towards T lymphocytes comprising contacting said T lymphocytes with a sufficient amount of an antibody specific for es-LAPase, an inhibitor of LAPase and an anti-estrogen compound.
Further according to the present invention there is provided a method for preventing or reducing HIV infection comprising administering to a patient in need thereof, a pharmaceutically effective amount of a composition which comprises an antibody specific to es-LAPase and a pharmaceutically acceptable carrier.
Also provided in this invention is a method for preventing or reducing HIV infection comprising administering to a patient in need thereof, a pharmaceutically effective amount of a composition which comprises an inhibitor of LAPase and a pharmaceutically acceptable carrier.
This invention is also directed to a method for preventing or reducing HIV infection comprising administering to a patient in need thereof, a pharmaceutically effective amount of a composition which comprises an antibody specific to es-LAPase and an inhibitor of LAPase together with a pharmaceutically acceptable carrier.
This invention is also directed to a method for preventing or reducing HIV infection comprising administering to a patient in need thereof, a pharmaceutically effective amount of a composition which comprises an antibody specific to es-LAPase, an inhibitor of LAPase and an anti-estrogen compound together with a pharmaceutically acceptable carrier.
Also according to the present invention there is provided a composition comprising an antibody specific to es-LAPase and an inhibitor of LAPase.
Also according to the present invention there is provided a composition comprising an antibody specific to es-LAPase, an inhibitor of LAPase and an anti-estrogen compound.